Drug addiction is one of the most costly and devastating medical problems in the United States today. Hundreds of thousands of people die from drug or alcohol related illnesses each year. The goal of this proposal is to determine if protein kinase M zeta (PKMz), a molecule implicated in maintaining long term memory in the hippocampus, contributes to sustaining memories acquired during drug use. Our preliminary data suggests that PKMz is present in the amygdala and maintains long term memory for an associative, cued conditioning task. It is not known if the same mechanisms governing a fear based associative task are also important for a reward based, conditioned place preference task. In this paradigm a rat learns.to associate a positive reinforcer, in this case cocaine with one of the two arms of a maze. The two arms are distinctive from one another through the use of a different tactile, olfactory, and visual cues. Testing is a measure of the time each rat spends in the arm previously associated with the rewarding drug cocaine. To investigate the role PKMz may have on the-long term memory, a pseudosubstrate inhibitory peptide (zip), previously shown to be a PKMz specific inhibitor, will be bilaterally infused into the basal lateral amygdala twenty-two hours after each cocaine-arm training trial. Testing for place preference will occur one day upon completion of training. In parallel several control experiments will be done to determine if zip is affecting memory or some other behavioral component such as the experience of the primary reward. In addition to behavior, expression of protein and mRNA levels will be determined at different time points following the CPP task by northern, western, immunohistochemistry and in-situ hybridization experiments. Understanding the mechanisms which sustain pathological drug use is critical to disrupting the addictive cycle. Cocaine in particular is widely used in the United States and unlike other substances of abuse, lack any pharmacological intervention. The goal of the present work is to uncover the critical biochemical pathways that are altered by addiction and construct possible clinical interventions. 17b. Cocaine is a widely abused drug and continues to be an important public health problem with 2.3 million current cocaine users in the U.S. alone. Unfortunately, no effective pharmacological treatments are available for cocaine dependence. The goal of the present proposal is to attempt to identify the underlying biological mechanisms contributing to the addiction to cocaine. We believe that a particular molecule called protein kinase m zeta that is critical for long term memory may, through memory mechanisms contribute to craving, relapse and ultimately the cycle of addiction.